Proteins containing a RhoGAP (Rho GTPase activating protein) domain usually function to catalyze the hydrolysis of GTP that is bound to Rho, Rac and/or Cdc42, inactivating these regulators of the actin cytoskeleton. Using database searches, at least 53 distinct RhoGAP domain-containing proteins are likely to be encoded in human DNA. Phylogenetic analysis of only the RhoGAP domains divides these proteins into distinct families that appear to be functionally related. We also review the current understanding of the structure and likely functions of these human proteins. The presence of RhoGAP domains in a number of different human proteins suggests that cytoskeletal changes, regulated by Rho GTPase, may be integrated with many different signaling pathways.